Heteroaromatic compounds useful for the treatment of prolferative diseases

ABSTRACT

The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of a kinase, such as a cyclin-dependent kinase (CDK) (e.g., cyclin-dependent kinase 7 (CDK7)), and therefore, in duce cellular apoptosis and/or inhibit transcription in the subject.

BACKGROUND OF THE INVENTION

The members of the cyclin-dependent kinase (CDK) family play criticalregulatory roles in proliferation. Unique among the mammalian CDKs, CDK7has consolidated kinase activities, regulating both the cell cycle andtranscription. In the cytosol, CDK7 exists as a heterotrimeric complexand is believed to function as a CDK1/2-activating kinase (CAK), wherebyphosphorylation of conserved residues in CDK1/2 by CDK7 is required forfull catalytic CDK activity and cell cycle progression. In the nucleus,CDK7 forms the kinase core of the RNA polymerase (RNAP) II generaltranscription factor complex and is charged with phosphorylating theC-terminal domain (CTD) of RNAP II, a requisite step in genetranscriptional initiation Together, the two functions of CDK7, i.e.,CAK and CTD phosphorylation, support critical facets of cellularproliferation, cell cycling, and transcription.

Disruption of RNAP II CTD phosphorylation has been shown topreferentially affect proteins with short half-lives, including those ofthe anti-apoptotic BCL-2 family. Cancer cells have demonstrated theability to circumvent pro-cell death signaling through upregulation ofBCL-2 family members. Therefore, inhibition of human CDK7 kinaseactivity is likely to result in anti-proliferative activity.

The discovery of selective inhibitors of CDK7 has been hampered by thehigh sequence and structural similarities of the kinase domain of CDKfamily members. Therefore, there is a need for the discovery anddevelopment of selective CDK7 inhibitors. Such CKD7 inhibitors holdpromise as a therapeutic agent for the treatment of CLL and othercancers.

SUMMARY OF THE INVENTION

The present invention provides CDK inhibitors, more particularly CDK7,CDK12, and CDK13 inhibitors, and in particular selective CDK7 inhibitorsof Formula (I), and pharmaceutically acceptable salts, solvates,hydrates, tautomers, stereoisomers, isotopically labeled derivatives,and compositions thereof. The present invention further provides methodsof using the compounds of the invention, and pharmaceutically acceptablesalts, solvates, hydrates, tautomers, stereoisomers, isotopicallylabeled derivatives, and compositions thereof, to study the inhibitionof CDK7 and other CDK family members, and as therapeutics for theprevention and/or treatment of diseases associated with overexpressionand/or aberrant activity of CDK7 and other CDK family members. Incertain embodiments, the inventive compounds are used for the preventionand/or treatment of proliferative diseases (e.g., cancers (e.g.,leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis,inflammatory diseases, autoinflammatory diseases, and autoimmunediseases) in a subject.

In one aspect, the present invention provides compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, hydrates, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinRing A, W, X, R^(1b), R², R³, R⁴, R⁷, R⁸, m, n and subvariables thereofare as defined herein.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, hydrate, tautomer, stereoisomer, orisotopically labeled derivative thereof, and optionally apharmaceutically acceptable excipient. In certain embodiments, thepharmaceutical compositions described herein include a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, hydrate, tautomer, stereoisomer, orisotopically labeled derivative thereof. The pharmaceutical compositionmay be useful for treating and/or preventing a proliferative orinfectious disease.

In another aspect, the present invention provides methods for treatingand/or preventing proliferative diseases. Exemplary proliferativediseases include cancer (e.g., leukemia, melanoma, multiple myeloma),benign neoplasm, angiogenesis, inflammatory diseases, autoinflammatorydiseases, and autoimmune diseases. In other embodiments, the presentinvention provides methods for treating and/or preventing an infectiousdisease (e.g., a viral infection).

In still another aspect, the present invention provides methods ofdown-regulating the expression of a CDK in a biological sample orsubject, more specifically CDK7.

Another aspect of the invention relates to methods of inhibiting theactivity of CDK7 in a biological sample or subject.

The present invention also provides methods of inhibiting cell growth ina biological sample or subject.

In still another aspect, the present invention provides methods ofinducing apoptosis of a cell in a biological sample or a subject.

In yet another aspect, the present invention provides compounds ofFormula (I), and pharmaceutically acceptable salts, solvates, hydrates,tautomers, stereoisomers, isotopically labeled derivatives, andcompositions thereof, for use in the treatment of a proliferativedisease in a subject.

In yet another aspect, the present invention provides compounds ofFormula (I), and pharmaceutically acceptable salts, solvates, hydrates,tautomers, stereoisomers, isotopically labeled derivatives, andcompositions thereof, for use in the treatment or prevention of aninfectious disease in a subject. In certain embodiments, the infectiousdisease is a viral infection.

Another aspect of the present invention relates to kits comprising acontainer with a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, hydrate, tautomer, stereoisomer, orisotopically labeled derivative thereof, or a pharmaceutical compositionthereof. In certain embodiments, the kits described herein furtherinclude instructions for administering the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, hydrate, tautomer,stereoisomer, or isotopically labeled derivative thereof, or thepharmaceutical composition thereof.

The details of one or more embodiments of the invention are set forthherein. Other features, objects, and advantages of the invention will beapparent from the Detailed Description, the Figures, the Examples, andthe Claims.

DEFINITIONS

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention.

Where a particular enantiomer is preferred, it may, in some embodimentsbe provided substantially free of the corresponding enantiomer, and mayalso be referred to as “optically enriched.” “Optically-enriched,” asused herein, means that the compound is made up of a significantlygreater proportion of one enantiomer. In certain embodiments thecompound is made up of at least about 90% by weight of a preferredenantiomer. In other embodiments the compound is made up of at leastabout 95%, 98%, or 99% by weight of a preferred enantiomer. Preferredenantiomers may be isolated from racemic mixtures by any method known tothose skilled in the art, including chiral high pressure liquidchromatography (HPLC) and the formation and crystallization of chiralsalts or prepared by asymmetric syntheses. See, for example, Jacques etal., Enantiomers, Racemates and Resolutions (Wiley Interscience, NewYork, 1981); Wilen, et al., Tetrahedron 33:2725 (1977); Eliel, E. L.Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L.Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

The term “aliphatic” or “aliphatic group”, as used herein, denotes ahydrocarbon moiety that may be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spiro-fusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-6 carbon atoms. In someembodiments, aliphatic groups contain 1-4 carbon atoms, and in yet otherembodiments aliphatic groups contain 1-3 carbon atoms. Suitablealiphatic groups include, but are not limited to, linear or branched,alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “alkyl,” as used herein, refers to a monovalent saturated,straight- or branched-chain hydrocarbon such as a straight or branchedgroup of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂alkyl, C₁-C₁₀ alkyl, and C₁-C₆ alkyl, respectively. Examples of alkylgroups include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pentyl,tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, and the like.

The terms “alkenyl” and “alkynyl” are art-recognized and refer tounsaturated aliphatic groups analogous in length and possiblesubstitution to the alkyls described above, but that contain at leastone double or triple bond, respectively. Exemplary alkenyl groupsinclude, but are not limited to, —CH═CH₂ and —CH₂CH═CH₂.

The term “alkylene” refers to the diradical of an alkyl group.

The terms “alkenylene” and “alkynylene” refer to the diradicals of analkenyl and an alkynyl group, respectively.

The term “methylene unit” refers to a divalent —CH₂— group present in analkyl, alkenyl, alkynyl, alkylene, alkenylene, or alkynylene moiety.

The term “carbocyclic ring system”, as used herein, means a monocyclic,bicyclic or polycyclic hydrocarbon ring system, wherein each ring iseither completely saturated or contains one or more units ofunsaturation, but where no ring is aromatic.

The term “carbocyclyl” refers to a radical of a carbocyclic ring systemas defined above. Representative carbocyclyl groups include cycloalkylgroups (e.g., cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl and thelike), and cycloalkenyl groups (e.g., cyclopentenyl, cyclohexenyl,cyclopentadienyl, and the like).

The term “aromatic ring system” is art-recognized and refers to amonocyclic, bicyclic or polycyclic hydrocarbon ring system, wherein atleast one ring is aromatic.

The term “aryl” refers to a radical of an aromatic ring system.Representative aryl groups include fully aromatic ring systems, such asphenyl, naphthyl, and anthracenyl, and ring systems where an aromaticcarbon ring is fused to one or more non-aromatic carbon rings, such asindanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl, and thelike.

The term “heteroaromatic ring system” is art-recognized and refers tomonocyclic, bicyclic or polycyclic ring system wherein at least one ringis both aromatic and comprises a heteroatom; and wherein no other ringsare heterocyclyl (as defined below). In certain instances, a ring whichis aromatic and comprises a heteroatom contains 1, 2, 3, or 4independently selected ring heteroatoms in such ring.

The term “heteroaryl” refers to a radical of a heteroaromatic ringsystem. Representative heteroaryl groups include ring systems where (i)each ring comprises a heteroatom and is aromatic, e.g., imidazolyl,oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenyl pyrazolyl,pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolizinyl, purinyl,naphthyridinyl, and pteridinyl; (ii) each ring is aromatic orcarbocyclyl, at least one aromatic ring comprises a heteroatom and atleast one other ring is a hydrocarbon ring or e.g., indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one,5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl; and(iii) each ring is aromatic or carbocyclyl, and at least one aromaticring shares a bridgehead heteroatom with another aromatic ring, e.g.,4H-quinolizinyl. In certain embodiments, the heteroaryl is a monocyclicor bicyclic ring, wherein each of said rings contains 5 or 6 ring atomswhere 1, 2, 3, or 4 of said ring atoms are a heteroatom independentlyselected from N, O, and S.

The term “heterocyclic ring system” refers to monocyclic, bicyclic andpolycyclic ring systems where at least one ring is saturated orpartially unsaturated (but not aromatic) and comprises a heteroatom. Aheterocyclic ring system can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted.

The term “heterocyclyl” refers to a radical of a heterocyclic ringsystem. Representative heterocyclyls include ring systems in which (i)every ring is non-aromatic and at least one ring comprises a heteroatom,e.g., tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl,dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl,and quinuclidinyl; (ii) at least one ring is non-aromatic and comprisesa heteroatom and at least one other ring is an aromatic carbon ring,e.g., 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and(iii) at least one ring is non-aromatic and comprises a heteroatom andat least one other ring is aromatic and comprises a heteroatom, e.g.,3,4-dihydro-1H-pyrano[4,3-c]pyridine, and1,2,3,4-tetrahydro-2,6-naphthyridine. In certain embodiments, theheterocyclyl is a monocyclic or bicyclic ring, wherein each of saidrings contains 3-7 ring atoms where 1, 2, 3, or 4 of said ring atoms area heteroatom independently selected from N, O, and S.

The term “saturated heterocyclyl” refers to a radical of heterocyclicring system wherein every ring is saturated, e.g., tetrahydrofuran,tetrahydro-2H-pyran, pyrrolidine, piperidine and piperazine.

“Partially unsaturated” refers to a group that includes at least onedouble or triple bond. A “partially unsaturated” ring system is furtherintended to encompass rings having multiple sites of unsaturation, butis not intended to include aromatic groups (e.g., aryl or heteroarylgroups) as herein defined. Likewise, “saturated” refers to a group thatdoes not contain a double or triple bond, i.e., contains all singlebonds.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted”, whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at eachposition. Combinations of substituents envisioned under this inventionare preferably those that result in the formation of stable orchemically feasible compounds. The term “stable”, as used herein, refersto compounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group (such as an alkyl, alkenyl, alkynyl,alkylene, alkenylene, alkynylene or the carbon atom of a carbocyclyl,aryl, heterocyclyl or heteroaryl) are independently deuterium; halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋ ₄SR^(∘); —(CH₂)₀₋₄Ph (where “Ph” isphenyl), which may be substituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph whichmay be substituted with R^(∘); —CH═CHPh, which may be substituted with—R^(∘); —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R^(∘) ₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃;—(CH₂)₀₋₄—C(O)—N(R^(∘))—S(O)₂—R^(∘), —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘)—, —SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘);—(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —(CH₂)₀₋₄OC(O)NR^(∘)₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘)₂; —OP(O)(OR^(∘) ₂; —SiR^(∘) ₃; —(C₁₋₄ straight orbranched)alkylene)O—N(R^(∘) ₂; or —(C₁₋₄ straight orbranched)alkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substitutedas defined below and is independently hydrogen, deuterium, C₁₋₆aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or, notwithstanding the definitionabove, two independent occurrences of R^(∘), taken together with theirintervening atom(s), form a 3-12-membered saturated, partiallyunsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, which may besubstituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently deuterium, halogen,—(CH₂)₀₋₂R^(),-(haloR^()), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(),—(CH₂)₀₋₂CH(OR^())₂; —O(haloR^()), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(),—(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(), —(CH₂)₀₋₂SR^(), —(CH₂)₀₋₂SH,—(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(), —(CH₂)₀₋₂NR^() ₂, —NO₂, —SiR^() ₃,—C(O)SR^(), —(C₁₋₄ straight or branched alkylene)C(O)OR^(), or—SSR^() wherein each R^() is unsubstituted or where preceded by “halo”is substituted only with one or more halogens, and is independentlyselected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. Suitabledivalent substituents on a saturated carbon atom of R^(∘) include ═O and═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R*is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include deuterium,halogen, —R^(), -(haloR^()), —OH, —OR^(), —O(haloR^()), —CN,—C(O)OH, —C(O)OR^(), —NH₂, —NHR^(), —NR^() ₂, or —NO₂, wherein eachR^() is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlydeuterium, halogen, —R^(), -(haloR^()), —OH, —OR^(), —O(haloR^()),—CN, —C(O)OH, —C(O)OR^(), —NH₂, —NHR^(), —NR^() ₂, or —NO₂, whereineach R^() is unsubstituted or where preceded by “halo” is substitutedonly with one or more halogens, and is independently C₁₋₄aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro,—Cl), bromine (bromo, —Br), or iodine (iodo, —I).

The term “one or more methylene units of the alkylene, alkenylene oralkynylene is optionally replaced with —O—, —S—, —S(═O)₂, or —NR^(X)—”as used herein means that none, one, more than one, or all of themethylene units present may be so replaced. Thus, for example, themoieties, —O—, —S—, and —NR^(X)— are included in this definition becausein each case they represent a C₁ alkylene (i.e., methylene) replacedwith —O—, —S—, or —NR^(X)—, respectively.

It should also be understood that reference to a variable or subvariablein Formula I (e.g., R², R⁴ or R⁵) being “an optionally substituted C₁-C₄alkylene, and an optionally substituted C₂-C₄ alkenylene or alkynylene,wherein: one or more methylene units of the alkylene, alkenylene oralkynylene other than a methylene unit bound to a nitrogen atom isoptionally and independently replaced with —O—, —S—, —N(R⁶)—, or—S(═O)₂—” is only intended to encompass chemically stable combinationsof optionally substitutions and replacements.

As used herein, the term “leaving group” is given its ordinary meaningin the art of synthetic organic chemistry and refers to an atom or agroup capable of being displaced by a nucleophile. Examples of suitableleaving groups include, but are not limited to, halogen (such as F, Cl,Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy,alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy),arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, andhaloformates. In some cases, the leaving group is a sulfonic acid ester,such as toluenesulfonate (tosylate, —OTs), methanesulfonate (mesylate,—OMs), p-bromobenzenesulfonyloxy (brosylate, —OBs), ortrifluoromethanesulfonate (triflate, —OTf). In some cases, the leavinggroup is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases,the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. Insome embodiments, the leaving group is a sulfonate-containing group. Insome embodiments, the leaving group is a tosylate group. The leavinggroup may also be a phosphineoxide (e.g., formed during a Mitsunobureaction) or an internal leaving group such as an epoxide or cyclicsulfate. Other non-limiting examples of leaving groups are water,ammonia, alcohols, ether moieties, thioether moieties, zinc halides,magnesium moieties, diazonium salts, and copper moieties.

These and other exemplary substituents are described in more detail inthe Detailed Description, Figures, Examples, and Claims. The inventionis not intended to be limited in any manner by the above exemplarylisting of substituents.

Other Definitions

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid, and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, ormalonic acid or by using other methods known in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ ⁻ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound that are associatedwith a solvent, usually by a solvolysis reaction. This physicalassociation may include hydrogen bonding. Conventional solvents includewater, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and thelike. The compounds of Formula (I) may be prepared, e.g., in crystallineform, and may be solvated. Suitable solvates include pharmaceuticallyacceptable solvates and further include both stoichiometric solvates andnon-stoichiometric solvates. In certain instances, the solvate will becapable of isolation, for example, when one or more solvent moleculesare incorporated in the crystal lattice of a crystalline solid.“Solvate” encompasses both solution-phase and isolable solvates.Representative solvates include hydrates, ethanolates, and methanolates.

The term “hydrate” refers to a compound which is associated with water.Typically, the number of the water molecules contained in a hydrate of acompound is in a definite ratio to the number of the compound moleculesin the hydrate. Therefore, a hydrate of a compound may be represented,for example, by the general formula R.x H₂O, wherein R is the compoundand wherein x is a number greater than 0. A given compound may form morethan one type of hydrates, including, e.g., monohydrates (x is 1), lowerhydrates (x is a number greater than 0 and smaller than 1, e.g.,hemihydrates (R.0.5 H₂O)), and polyhydrates (x is a number greater than1, e.g., dihydrates (R.2 H₂O) and hexahydrates (R.6 H₂O)).

The term “tautomers” refer to compounds that are interchangeable formsof a particular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of it electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenylnitromethane that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable minor images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult, or senior adult)) and/or othernon-human animals, for example, mammals (e.g., primates (e.g.,cynomolgus monkeys, rhesus monkeys); commercially relevant mammals suchas cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds(e.g., commercially relevant birds such as chickens, ducks, geese,and/or turkeys). In certain embodiments, the animal is a mammal. Theanimal may be a male or female and at any stage of development. Anon-human animal may be a transgenic animal.

The terms “administer,” “administering,” or “administration,” as usedherein refers to implanting, absorbing, ingesting, injecting, inhaling,or otherwise introducing an inventive compound, or a pharmaceuticalcomposition thereof.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a “pathological condition” (e.g., a disease, disorder, orcondition, or one or more signs or symptoms thereof) described herein.In some embodiments, “treatment,” “treat,” and “treating” require thatsigns or symptoms of the disease disorder or condition have developed orhave been observed. In other embodiments, treatment may be administeredin the absence of signs or symptoms of the disease or condition. Forexample, treatment may be administered to a susceptible individual priorto the onset of symptoms (e.g., in light of a history of symptoms and/orin light of genetic or other susceptibility factors). Treatment may alsobe continued after symptoms have resolved, for example, to delay orprevent recurrence.

As used herein, the terms “condition,” “disease,” and “disorder” areused interchangeably.

An “effective amount” of a compound of Formula (I) refers to an amountsufficient to elicit the desired biological response, i.e., treating thecondition. As will be appreciated by those of ordinary skill in thisart, the effective amount of a compound of Formula (I) may varydepending on such factors as the desired biological endpoint, thepharmacokinetics of the compound, the condition being treated, the modeof administration, and the age and health of the subject. An effectiveamount encompasses therapeutic and prophylactic treatment. For example,in treating cancer, an effective amount of an inventive compound mayreduce the tumor burden or stop the growth or spread of a tumor.

A “therapeutically effective amount” of a compound of Formula (I) is anamount sufficient to provide a therapeutic benefit in the treatment of acondition or to delay or minimize one or more symptoms associated withthe condition. In some embodiments, a therapeutically effective amountis an amount sufficient to provide a therapeutic benefit in thetreatment of a condition or to minimize one or more symptoms associatedwith the condition. A therapeutically effective amount of a compoundmeans an amount of therapeutic agent, alone or in combination with othertherapies, which provides a therapeutic benefit in the treatment of thecondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms orcauses of the condition, or enhances the therapeutic efficacy of anothertherapeutic agent.

A “prophylactically effective amount” of a compound of Formula (I) is anamount sufficient to prevent a condition, or one or more symptomsassociated with the condition or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the condition. Theterm “prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

A “proliferative disease” refers to a disease that occurs due toabnormal growth or extension by the multiplication of cells (Walker,Cambridge Dictionary of Biology; Cambridge University Press: Cambridge,UK, 1990). A proliferative disease may be associated with: 1) thepathological proliferation of normally quiescent cells; 2) thepathological migration of cells from their normal location (e.g.,metastasis of neoplastic cells); 3) the pathological expression ofproteolytic enzymes such as the matrix metalloproteinases (e.g.,collagenases, gelatinases, and elastases); or 4) the pathologicalangiogenesis as in proliferative retinopathy and tumor metastasis.Exemplary proliferative diseases include cancers (i.e., “malignantneoplasms”), benign neoplasms, angiogenesis, inflammatory diseases,autoinflammatory diseases, and autoimmune diseases.

The terms “neoplasm” and “tumor” are used herein interchangeably andrefer to an abnormal mass of tissue wherein the growth of the masssurpasses and is not coordinated with the growth of a normal tissue. Aneoplasm or tumor may be “benign” or “malignant,” depending on thefollowing characteristics: degree of cellular differentiation (includingmorphology and functionality), rate of growth, local invasion, andmetastasis. A “benign neoplasm” is generally well differentiated, hascharacteristically slower growth than a malignant neoplasm, and remainslocalized to the site of origin. In addition, a benign neoplasm does nothave the capacity to infiltrate, invade, or metastasize to distantsites. Exemplary benign neoplasms include, but are not limited to,lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheickeratoses, lentigos, and sebaceous hyperplasias. In some cases, certain“benign” tumors may later give rise to malignant neoplasms, which mayresult from additional genetic changes in a subpopulation of the tumor'sneoplastic cells, and these tumors are referred to as “pre-malignantneoplasms.” An exemplary pre-malignant neoplasm is a teratoma. Incontrast, a “malignant neoplasm” is generally poorly differentiated(anaplasia) and has characteristically rapid growth accompanied byprogressive infiltration, invasion, and destruction of the surroundingtissue. Furthermore, a malignant neoplasm generally has the capacity tometastasize to distant sites.

As used herein, the term “cancer” refers to a malignant neoplasm(Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins:Philadelphia, 1990). Exemplary cancers include, but are not limited to,acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer;angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma,hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliarycancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g.,adenocarcinoma of the breast, papillary carcinoma of the breast, mammarycancer, medullary carcinoma of the breast); brain cancer (e.g.,meningioma, glioblastomas, glioma (e.g., astrocytoma,oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor;cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma;chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer,rectal cancer, colorectal adenocarcinoma); connective tissue cancer;epithelial carcinoma; ependymoma; endothelio sarcoma (e.g., Kaposi'ssarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer(e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g.,adenocarcinoma of the esophagus, Barrett's adenocarcinoma); Ewing'ssarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma);familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g.,stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germcell cancer; head and neck cancer (e.g., head and neck squamous cellcarcinoma, oral cancer (e.g., oral squamous cell carcinoma), throatcancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngealcancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemiasuch as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL),acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronicmyelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chroniclymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomasuch as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) andnon-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large celllymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicularlymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas(e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma),primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacyticlymphoma (i.e., Waldenstrom's macroglobulinemia), hairy cell leukemia(HCL), immunoblastic large cell lymphoma, precursor B-lymphoblasticlymphoma and primary central nervous system (CNS) lymphoma; and T-cellNHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheralT-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma,extranodal natural killer T-cell lymphoma, enteropathy type T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplasticlarge cell lymphoma); a mixture of one or more leukemia/lymphoma asdescribed above; and multiple myeloma (MM)), heavy chain disease (e.g.,alpha chain disease, gamma chain disease, mu chain disease);hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastictumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastomaa.k.a. Wilms' tumor, renal cell carcinoma); liver cancer (e.g.,hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g.,bronchogenic carcinoma, small cell lung cancer (SCLC), non-small celllung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS);mastocytosis (e.g., systemic mastocytosis); muscle cancer;myelodysplastic syndrome (MDS); mesothelioma; myeloproliferativedisorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis(ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF),chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML),chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES));neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreaticneuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarianembryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma;pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductalpapillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer(e.g., Paget's disease of the penis and scrotum); pinealoma; primitiveneuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplasticsyndromes; intraepithelial neoplasms; prostate cancer (e.g., prostateadenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer;skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA),melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g.,appendix cancer); soft tissue sarcoma (e.g., malignant fibroushistiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor(MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous glandcarcinoma; small intestine cancer; sweat gland carcinoma; synovioma;testicular cancer (e.g., seminoma, testicular embryonal carcinoma);thyroid cancer (e.g., papillary carcinoma of the thyroid, papillarythyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer;vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

The term “angiogenesis” refers to the formation and the growth of newblood vessels. Normal angiogenesis occurs in the healthy body of asubject for healing wounds and for restoring blood flow to tissues afterinjury. The healthy body controls angiogenesis through a number ofmeans, e.g., angiogenesis-stimulating growth factors and angiogenesisinhibitors. Many disease states, such as cancer, diabetic blindness,age-related macular degeneration, rheumatoid arthritis, and psoriasis,are characterized by abnormal (i.e., increased or excessive)angiogenesis. Abnormal angiogenesis refers to angiogenesis greater thanthat in a normal body, especially angiogenesis in an adult not relatedto normal angiogenesis (e.g., menstruation or wound healing). Abnormalangiogenesis can provide new blood vessels that feed diseased tissuesand/or destroy normal tissues, and in the case of cancer, the newvessels can allow tumor cells to escape into the circulation and lodgein other organs (tumor metastases).

As used herein, an “inflammatory disease” refers to a disease caused by,resulting from, or resulting in inflammation. The term “inflammatorydisease” may also refer to a dysregulated inflammatory reaction thatcauses an exaggerated response by macrophages, granulocytes, and/orT-lymphocytes leading to abnormal tissue damage and/or cell death. Aninflammatory disease can be either an acute or chronic inflammatorycondition and can result from infections or non-infectious causes.Inflammatory diseases include, without limitation, atherosclerosis,arteriosclerosis, autoimmune disorders, multiple sclerosis, systemiclupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis,degenerative arthritis, tendonitis, bursitis, psoriasis, cysticfibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis,Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis(scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis,pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis,Hashimoto's thyroiditis, Graves' disease, Goodpasture's disease, mixedconnective tissue disease, sclerosing cholangitis, inflammatory boweldisease, Crohn's disease, ulcerative colitis, pernicious anemia,inflammatory dermatoses, usual interstitial pneumonitis (UIP),asbestosis, silicosis, bronchiectasis, berylliosis, talcosis,pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia,lymphoid interstitial pneumonia, giant cell interstitial pneumonia,cellular interstitial pneumonia, extrinsic allergic alveolitis,Wegener's granulomatosis and related forms of angiitis (temporalarteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis,delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis),pneumonia, respiratory tract inflammation, Adult Respiratory DistressSyndrome (ARDS), encephalitis, immediate hypersensitivity reactions,asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever,glomerulonephritis, pyelonephritis, cellulitis, cystitis, chroniccholecystitis, ischemia (ischemic injury), reperfusion injury, allograftrejection, host-versus-graft rejection, appendicitis, arteritis,blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis,chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis,endocarditis, endometritis, enteritis, enterocolitis, epicondylitis,epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis,gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis,nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis,phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis,sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis,urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis,angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporalarteritis, transverse myelitis, necrotizing fasciitis, and necrotizingenterocolitis.

As used herein, an “autoimmune disease” refers to a disease arising froman inappropriate immune response of the body of a subject againstsubstances and tissues normally present in the body. In other words, theimmune system mistakes some part of the body as a pathogen and attacksits own cells. This may be restricted to certain organs (e.g., inautoimmune thyroiditis) or involve a particular tissue in differentplaces (e.g., Goodpasture's disease which may affect the basementmembrane in both the lung and kidney). The treatment of autoimmunediseases is typically with immunosuppression, e.g., medications whichdecrease the immune response. Exemplary autoimmune diseases include, butare not limited to, glomerulonephritis, Goodpasture's syndrome,necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemiclupus erythematosis, rheumatoid, arthritis, psoriatic arthritis,systemic lupus erythematosis, psoriasis, ulcerative colitis, systemicsclerosis, dermatomyositis/polymyositis, anti-phospholipid antibodysyndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis(e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis,Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosingspondylitis, Lyme arthritis, Guillain-Barré syndrome, Hashimoto'sthyroiditis, and cardiomyopathy.

The term “autoinflammatory disease” refers to a category of diseasesthat are similar but different from autoimmune diseases.Autoinflammatory and autoimmune diseases share common characteristics inthat both groups of disorders result from the immune system attacking asubject's own tissues and result in increased inflammation. Inautoinflammatory diseases, a subject's innate immune system causesinflammation for unknown reasons. The innate immune system reacts eventhough it has never encountered autoantibodies or antigens in thesubject. Autoinflammatory disorders are characterized by intenseepisodes of inflammation that result in such symptoms as fever, rash, orjoint swelling. These diseases also carry the risk of amyloidosis, apotentially fatal buildup of a blood protein in vital organs.Autoinflammatory diseases include, but are not limited to, familialMediterranean fever (FMF), neonatal onset multisystem inflammatorydisease (NOMID), tumor necrosis factor (TNF) receptor-associatedperiodic syndrome (TRAPS), deficiency of the interleukin-1 receptorantagonist (DIRA), and Behçet's disease.

The term “biological sample” refers to any sample including tissuesamples (such as tissue sections and needle biopsies of a tissue); cellsamples (e.g., cytological smears (such as Pap or blood smears) orsamples of cells obtained by microdissection); samples of wholeorganisms (such as samples of yeasts or bacteria); or cell fractions,fragments or organelles (such as obtained by lysing cells and separatingthe components thereof by centrifugation or otherwise). Other examplesof biological samples include blood, serum, urine, semen, fecal matter,cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus,biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy),nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccalswabs), or any material containing biomolecules that is derived from afirst biological sample. Biological samples also include thosebiological samples that are transgenic, such as transgenic oocyte, spermcell, blastocyst, embryo, fetus, donor cell, or cell nucleus.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION Compounds

In one aspect of the present invention, provided are compounds ofFormula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer,stereoisomer, or isotopically labeled derivative thereof, wherein:

ring A is an optionally substituted heteroaryl ring of any one of theFormulae (i-1)-(i-6):

wherein:

each instance of V¹, V², V³, V⁴, V⁵, V⁶, V⁷, V⁸, V⁹, V¹⁰, V¹¹, V¹², V¹³,V¹⁴ and V¹⁵ is independently O, S, N, N(R^(A1)), C, or C(R^(A2));

each instance of R^(A1) is independently selected from hydrogen,deuterium, optionally substituted acyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl;

each instance of R^(A2) is independently selected from hydrogen,deuterium, halogen, —CN, optionally substituted acyl, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —OR^(A2a), —N(R^(A2a))₂, and —SR^(A2a), whereineach occurrence of R^(A2a) is independently selected from hydrogen,optionally substituted acyl, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or

any two R^(A1), any two R^(A2), or one R^(A1) and one R^(A2) are joinedto form an optionally substituted carbocyclic, optionally substitutedheterocyclic, optionally substituted aryl, or optionally substitutedheteroaryl ring;

each X is independently selected from N and CH, wherein at least one Xis N;

W is selected from N and C(R^(1a));

each of R^(1a), if present, and R^(1b) is independently selected fromhydrogen, deuterium, halogen, optionally substituted acyl, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —OR^(B1a), —N(R^(B1a))₂, and —SR^(B1a),wherein each occurrence of R^(B1a) is independently selected fromhydrogen, optionally substituted acyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, or

R^(1a) and R^(1b) are joined to form an optionally substitutedcarbocyclic, optionally substituted heterocyclic, optionally substitutedaryl, or optionally substituted heteroaryl ring;

R² is an optionally substituted C₁-C₄ alkylene or an optionallysubstituted C₂-C₄ alkenylene or alkynylene, wherein one or moremethylene units of the alkylene, alkenylene or alkynylene are optionallyand independently replaced with —O—, —S—, or —N(R⁶)—;

each instance of R³, if present, is independently selected fromdeuterium, halogen, optionally substituted acyl, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(C1), —N(R^(C1))₂, and —SR^(C1), wherein each occurrence of R^(C1)is independently selected from hydrogen, optionally substituted acyl,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or

two R³ groups bound to the same ring carbon atom are taken together toform ═O, or

two R³ groups bound to the same or different ring carbon atoms arejoined to form an optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl ring;

R⁴ is selected from a bond, an optionally substituted C₁-C₄ alkylene,and an optionally substituted C₂-C₄ alkenylene or alkynylene, wherein:

one or more methylene units of the alkylene, alkenylene or alkynyleneother than a methylene unit bound to a nitrogen atom is optionally andindependently replaced with —O—, —S—, —N(R⁶)—, or —S(═O)₂—, and

two substituents on either the same or adjacent carbon atoms in thealkylene, alkenylene or alkynylene are taken together to form anoptionally substituted carbocyclic or optionally substitutedheterocyclic ring;

each R⁶ is independently selected from hydrogen, and —C₁-C₆ alkyl;

R⁷ is any one of the Formulae (ii-1)-(ii-20):

wherein:

L³ is a bond, an optionally substituted C₁-C₄ alkylene, or an optionallysubstituted C₂-C₄ alkenylene or alkynylene, wherein one or moremethylene units of the alkylene, alkenylene or alkynylene are optionallyand independently replaced with —O—, —S—, or —N(R⁶)—;

L⁴ is a bond, an optionally substituted C₁-C₄ alkylene, or an optionallysubstituted C₂-C₄ alkenylene or alkynylene;

R^(E1) is selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —CH₂OR^(E1a), —CH₂N(R^(E1a))₂,—CH₂SR^(E1a), —OR^(E1a), —N(R^(E1a))₂, —Si(R^(E1a))₃, and —Si(R^(E1a))₃,wherein each occurrence of R^(E1a) is independently selected from thegroup consisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or two R^(E1a)groups are joined to form an optionally substituted heterocyclic ring;

R^(E2) is selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —CH₂OR^(E2a), —CH₂N(R^(E2a))₂,—CH₂SR^(E2a), —OR^(E2a), —N(R^(E2a))₂, and —SR^(E2a), wherein eachoccurrence of R^(E2a) is independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or two R^(E2a)groups are joined to form an optionally substituted heterocyclic ring;

R^(E3) is selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —CH₂OR^(E3a), —CH₂N(R^(E3a))₂,—CH₂SR^(E3a), —OR^(E3a), —N(R^(E3a))₂, and —SR^(E3a), wherein eachoccurrence of R^(E3a) is independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or two R^(E3a)groups are joined to form an optionally substituted heterocyclic ring;

optionally R^(E1) and R^(E3), or R^(E2) and R^(E3), or R^(E1) and R^(E2)are joined to form an optionally substituted carbocyclic or optionallysubstituted heterocyclic ring;

R^(E4) is a leaving group;

R^(E5) is selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —CH₂OR^(E5a), —CH₂N(R^(E5a))₂,—CH₂SR^(E5a), —OR^(E5a), —N(R^(E5a))₂, and —SR^(E5a), wherein eachoccurrence of R^(E5a) is independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or two R^(E5a)groups are joined to form an optionally substituted heterocyclic ring;

-   -   Y is O, S, or NR^(E6), wherein R^(E6) is hydrogen, substituted        or unsubstituted C₁₋₆ alkyl, or a nitrogen protecting group;    -   a is 1 or 2;    -   z is 0, 1, 2, 3, 4, 5, or 6.

each instance of R⁸, if present, is independently selected fromdeuterium, halogen, optionally substituted acyl, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(D1), —N(R^(D1))₂, and —SR^(D1), wherein each occurrence of R^(D1)is independently selected from hydrogen, optionally substituted acyl,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, and optionally substituted aryl, optionallysubstituted heteroaryl, or

two R⁸ groups are joined to form an optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl, oroptionally substituted heteroaryl ring;

m is 0, 1, 2, 3 or 4; and

n is 0, 1, 2, 3, 4, 5 or 6.

In certain embodiments, provided in the present invention are compoundsof Formula (I), and pharmaceutically acceptable salts thereof.

In certain embodiments, no more than three of V¹, V², V³, V⁴, V⁵, V⁶,V⁷, V⁸, and V⁹ are each independently selected from the group consistingof O, S, N, and N(R^(A1)).

In certain embodiments, two of V¹, V², V³, V⁴, V⁵, V⁶, V⁷, V⁸, and V⁹are each independently selected from the group consisting of N andN(R^(A1)) and the rest of V¹, V², V³, V⁴, V⁵, V⁶, V⁷, V⁸, and V⁹ areeach independently C or C(R^(A2)). In one aspect of these embodiments,one of V¹, V², or V³ is N(R^(A1)); one of V¹, V², or V³ is C; one of V¹,V², and V³ is C(R^(A2)); one of V⁴, V⁵, V⁶, or V⁷ is N, the rest of V⁴,V⁵, V⁶, and V⁷ are C(R^(A2)); and V⁸ and V⁹ are C.

In certain embodiments, one of V¹, V², V³, V⁴, V⁵, V⁶, V⁷, V⁸, and V⁹ isN or N(R^(A1)) and the rest of V¹, V², V³, V⁴, V⁵, V⁶, V⁷, V⁸, and V⁹are each independently C or C(R^(A2)). In one aspect of theseembodiments, one of V¹, V², or V³ is N(R^(A1)); one of V¹, V², or V³ isC; one of V¹, V², and V³ is C(R^(A2)); each of V⁴, V⁵, V⁶, and V⁷ areC(R^(A2)); and V⁸ and V⁹ are C.

In certain embodiments ring A is

In one aspect of these embodiments, ring A is

In certain embodiments ring A is

In one aspect of these embodiments, ring A is

In certain embodiments, each R^(A1) is independently selected fromhydrogen, or C₁₋₆ alkyl. In certain embodiments, all instances of R^(A1)are hydrogen.

In certain embodiments, each R^(A2) is independently selected fromhydrogen, halogen, and optionally substituted C₁-C₆ alkyl, andoptionally substituted aryl. In one aspect of these embodiments, allinstances of R^(A2) are hydrogen.

In certain embodiments, W is N.

In certain embodiments, W is C(R^(1a)).

In certain embodiments, each X is nitrogen. In one aspect of theseembodiments, each X is nitrogen and W is C(R^(1a)).

In certain embodiments, R^(1a) is selected from selected from hydrogen,halo, —OH, —C₁-C₃ alkyl, halo-substituted —C₁-C₃ alkyl, —O—C₁-C₃ alkyl,halo-substituted —O—C₁-C₃ alkyl, —CN, —NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃alkyl)₂, and C₃-C₆ cycloalkyl. In one aspect of these embodiments,R^(1a) is selected from halo, —CN and C₁-C₃ alkyl. In a more specificaspect of these embodiments, R^(1a) is selected from chloro, —CN and—CH₃. In an even more specific aspect of these embodiments, R^(1a) ischloro.

In certain embodiments, R^(1b) is selected from selected from hydrogen,halo, —OH, —C₁-C₃ alkyl, halo-substituted —C₁-C₃ alkyl, —O—C₁-C₃ alkyl,halo-substituted —O—C₁-C₃ alkyl, —CN, —NH₂, —NH(C₁-C₃ alkyl), and—N(C₁-C₃ alkyl)₂. In one aspect of these embodiments, R^(1b) ishydrogen.

In certain embodiments, R² is selected from —NH—; —N(C₁-C₃ alkyl)-;—NH—CH₂— **; and C₁-C₂ alkylene optionally substituted with 1 to 4substituents independently selected from halo, —OH, —C₁-C₃ alkyl,halo-substituted —C₁-C₃ alkyl, —O—C₁-C₃ alkyl, halo-substituted —O—C₁-C₃alkyl, —CN, —NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂, wherein “**”represents a portion of R² bound to piperidin-1,3-diyl. In a morespecific aspect of these embodiments, R² is selected from —NH— and—NH—CH₂—**. In an even more specific aspect of these embodiments, R² is—NH—.

In certain embodiments, R⁴ is selected from —S(═O)₂—, or C₁-C₂ alkyleneoptionally substituted with 1 to 4 substituents independently selectedfrom halo, ═O, —OH, —C₁-C₃ alkyl, halo-substituted —C₁-C₃ alkyl,—O—C₁-C₃ alkyl, halo-substituted —O—C₁-C₃ alkyl, —CN, —NH₂, —NH(C₁-C₃alkyl), and —N(C₁-C₃ alkyl)₂, wherein one methylene unit in the alkyleneis optionally replaced with —N(R⁶)—. In a more specific aspect of theseembodiments, R⁴ is —C(O)— or ‡‡—C(O)—NH—, wherein “‡‡” represents aportion of R⁴ bound to piperidin-1,3-diyl. In another specific aspect ofthese embodiments, R⁴ is —(CH₂)—.

In certain embodiments, R³ is absent (i.e., n is 0), or is selected fromhalo, —OH, —C₁-C₃ alkyl, halo-substituted —C₁-C₃ alkyl, —O—C₁-C₃ alkyl,halo-substituted —O—C₁-C₃ alkyl, —CN, —NH₂, —NH(C₁-C₃ alkyl), and—N(C₁-C₃ alkyl)₂, or two R³ bound to the same ring carbon atom are takentogether to form ═O. In a more specific aspect, R³ is absent (i.e., n is0).

In certain embodiments, each R⁶ present in a compound of Formula (I) isselected from hydrogen and —CH₃. In a more specific aspect of theseembodiments, each R⁶ is hydrogen.

In certain embodiments, R⁷ is located para or meta to R⁴. In certainembodiments, R⁷ is located para to R⁴. In one aspect of theseembodiments, R⁷ comprises L³ and L³ is —NR^(L3a)—. In a more specificaspect of these embodiments, R⁷ comprises L³ and L³ is —NH—. In anotheraspect of these embodiments, R⁷ comprises Y, and Y is ═O. In stillanother aspect of these embodiments, R⁷ comprises at least one ofR^(E1), R^(E2) and R^(E3) and one of the R^(E1), R^(E2) or R^(E3) thatis present is —CH₂N(R^(E1a))₂. In a more specific aspect of theseembodiments, R⁷ comprises at least one of R^(E1), R^(E2) and R^(E3); oneof the R^(E1), R^(E2) or R^(E3) that is present is —CH₂N(R^(E1a))₂; andeach R^(E1a) is independently an optionally substituted C₁-C₄ alkyl, orthe two R^(E1a) are taken together with the nitrogen atom to which theyare bound to form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl.

In certain embodiments, R⁷ is

In a more specific aspect of these embodiments, R⁷ is

In an even more specific aspect of these embodiments, R⁷ is

wherein each R^(E1a) is independently an optionally substituted C₁-C₄alkyl, or the two R^(E1a) are taken together with the nitrogen atom towhich they are bound to form an optionally substituted heterocyclyl oran optionally substituted heteroaryl. In a further more specific aspectof these embodiments, R⁷ is para to R⁴ and is selected from4-dimethylaminobut-2-enamido, 4-morpholin-4-ylbut-2-enamido,4-pyrrolidin-1-ylbut-2-enamido, 4-1H-imidazo-1-ylbut-2-enamido,4-(4-methylpiperazin-1-yl)but-2-enamido,4-(2-hydroxyethyl)(methyl)aminobut-2-enamido,4-dimethylaminobut-2-enamido, 4-dimethylaminobut-2-enamido,4-dimethylaminobut-2-enamido, and 4-dimethylaminobut-2-enamido. In aneven more specific aspect of these embodiments, R⁷ is para to R⁴ and is4-dimethylaminobut-2-enamido.

In certain embodiments, m is 0 or 1; and the single R⁸, if present, isselected C₁-C₄ alkyl and halogen. In a more specific aspect of theseembodiments, R⁸ is absent (i.e., m is 0).

Although, as indicated above, various embodiments and aspects thereoffor a variable in Formula (I) may be selected from a group of chemicalmoieties, the invention also encompasses as further embodiments andaspects thereof situations where such variable is: a) selected from anysubset of chemical moieties in such a group; and b) any single member ofsuch a group.

Although various embodiments and aspects thereof are set forth (orimplied, as discussed in the preceding paragraph) individually for eachvariable in Formula (I) above, the invention encompasses all possiblecombinations of the different embodiments and aspects for each of thevariables in Formula (I).

In certain embodiments, the compound of Formula (I) is selected from:

and pharmaceutically acceptable salts, solvates, hydrates, tautomers,stereoisomers, and isotopically labeled derivatives of the foregoing.

Pharmaceutical Compositions, Kits, and Administration

The present invention provides pharmaceutical compositions comprising acompound of Formula (I), e.g., a compound of Formula (I), or apharmaceutically acceptable salt, solvate, hydrate, tautomer,stereoisomer, or isotopically labeled derivative thereof, as describedherein, and optionally a pharmaceutically acceptable excipient. Incertain embodiments, the pharmaceutical composition of the inventioncomprises a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and optionally a pharmaceutically acceptable excipient. Incertain embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, hydrate, tautomer, stereoisomer, orisotopically labeled derivative thereof, is provided in an effectiveamount in the pharmaceutical composition. In certain embodiments, theeffective amount is a therapeutically effective amount. In certainembodiments, the effective amount is a prophylactically effectiveamount.

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the compound of Formula (I) (the“active ingredient”) into association with a carrier and/or one or moreother accessory ingredients, and then, if necessary and/or desirable,shaping and/or packaging the product into a desired single- ormulti-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.As used herein, a “unit dose” is a discrete amount of the pharmaceuticalcomposition comprising a predetermined amount of the active ingredient.The amount of the active ingredient is generally equal to the dosage ofthe active ingredient which would be administered to a subject and/or aconvenient fraction of such a dosage such as, for example, one-half orone-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition of the invention will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.By way of example, the composition may comprise between 0.1% and 100%(w/w) active ingredient.

The term “pharmaceutically acceptable excipient” refers to a non-toxiccarrier, adjuvant, diluent, or vehicle that does not destroy thepharmacological activity of the compound with which it is formulated.Pharmaceutically acceptable excipients useful in the manufacture of thepharmaceutical compositions of the invention are any of those that arewell known in the art of pharmaceutical formulation and include inertdiluents, dispersing and/or granulating agents, surface active agentsand/or emulsifiers, disintegrating agents, binding agents,preservatives, buffering agents, lubricating agents, and/or oils.Pharmaceutically acceptable excipients useful in the manufacture of thepharmaceutical compositions of the invention include, but are notlimited to, ion exchangers, alumina, aluminum stearate, lecithin, serumproteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

Compositions of the present invention may be administered orally,parenterally (including subcutaneous, intramuscular, intravenous andintradermal), by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. In some embodiments,provided compounds or compositions are administrable intravenouslyand/or orally.

The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intraocular, intravitreal, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intraperitonealintralesional and intracranial injection or infusion techniques.Preferably, the compositions are administered orally, subcutaneously,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added. In some embodiments, aprovided oral formulation is formulated for immediate release orsustained/delayed release. In some embodiments, the composition issuitable for buccal or sublingual administration, including tablets,lozenges and pastilles. A provided compound can also be inmicro-encapsulated form.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. Pharmaceutically acceptable compositions of thisinvention may also be administered topically, especially when the targetof treatment includes areas or organs readily accessible by topicalapplication, including diseases of the eye, the skin, or the lowerintestinal tract. Suitable topical formulations are readily prepared foreach of these areas or organs.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions or in an ointment such aspetrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.

Compounds provided herein are typically formulated in dosage unit form,e.g., single unit dosage form, for ease of administration and uniformityof dosage. It will be understood, however, that the total daily usage ofthe compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular subjector organism will depend upon a variety of factors including the diseasebeing treated and the severity of the disorder; the activity of thespecific active ingredient employed; the specific composition employed;the age, body weight, general health, sex and diet of the subject; thetime of administration, route of administration, and rate of excretionof the specific active ingredient employed; the duration of thetreatment; drugs used in combination or coincidental with the specificactive ingredient employed; and like factors well known in the medicalarts.

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound(s), mode ofadministration, and the like. The desired dosage can be delivered threetimes a day, two times a day, once a day, every other day, every thirdday, every week, every two weeks, every three weeks, or every fourweeks. In certain embodiments, the desired dosage can be delivered usingmultiple administrations (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or moreadministrations).

In certain embodiments, an effective amount of a compound foradministration one or more times a day to a 70 kg adult human maycomprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg,about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosageform.

In certain embodiments, the compounds of Formula (I) may be at dosagelevels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg,from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kgto about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg,from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, ofsubject body weight per day, one or more times a day, to obtain thedesired therapeutic effect.

It will be appreciated that dose ranges as described herein provideguidance for the administration of provided pharmaceutical compositionsto an adult. The amount to be administered to, for example, a child oran adolescent can be determined by a medical practitioner or personskilled in the art and can be lower or the same as that administered toan adult.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionalpharmaceutical agents. The compounds or compositions can be administeredin combination with additional pharmaceutical agents that improve theirbioavailability, reduce and/or modify their metabolism, inhibit theirexcretion, and/or modify their distribution within the body. It willalso be appreciated that the therapy employed may achieve a desiredeffect for the same disorder, and/or it may achieve different effects.

The compound or composition can be administered concurrently with, priorto, or subsequent to, one or more additional pharmaceutical agents,which may be useful as, e.g., combination therapies. Pharmaceuticalagents include therapeutically active agents. Pharmaceutical agents alsoinclude prophylactically active agents. Each additional pharmaceuticalagent may be administered at a dose and/or on a time schedule determinedfor that pharmaceutical agent. The additional pharmaceutical agents mayalso be administered together with each other and/or with the compoundor composition described herein in a single dose or administeredseparately in different doses. The particular combination to employ in aregimen will take into account compatibility of the inventive compoundwith the additional pharmaceutical agents and/or the desired therapeuticand/or prophylactic effect to be achieved. In general, it is expectedthat the additional pharmaceutical agents utilized in combination beutilized at levels that do not exceed the levels at which they areutilized individually. In some embodiments, the levels utilized incombination will be lower than those utilized individually.

Exemplary additional pharmaceutical agents include, but are not limitedto, anti-proliferative agents, anti-cancer agents, anti-diabetic agents,anti-inflammatory agents, immunosuppressant agents, and a pain-relievingagent. Pharmaceutical agents include small organic molecules such asdrug compounds (e.g., compounds approved by the U.S. Food and DrugAdministration as provided in the Code of Federal Regulations (CFR)),peptides, proteins, carbohydrates, monosaccharides, oligosaccharides,polysaccharides, nucleoproteins, mucoproteins, lipoproteins, syntheticpolypeptides or proteins, small molecules linked to proteins,glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides,nucleosides, oligonucleotides, antisense oligonucleotides, lipids,hormones, vitamins, and cells.

Also encompassed by the invention are kits (e.g., pharmaceutical packs).The inventive kits may be useful for preventing and/or treating aproliferative disease (e.g., cancer (e.g., leukemia, melanoma, multiplemyeloma), benign neoplasm, angiogenesis, inflammatory disease,autoinflammatory disease, or autoimmune disease). The kits provided maycomprise an inventive pharmaceutical composition or compound and acontainer (e.g., a vial, ampule, bottle, syringe, and/or dispenserpackage, or other suitable container). In some embodiments, providedkits may optionally further include a second container comprising apharmaceutical excipient for dilution or suspension of an inventivepharmaceutical composition or compound. In some embodiments, theinventive pharmaceutical composition or compound provided in thecontainer and the second container are combined to form one unit dosageform.

Thus, in one aspect, provided are kits including a first containercomprising a compound described herein, or a pharmaceutically acceptablesalt, solvate, hydrate, tautomer, stereoisomer, and isotopically labeledderivative, or a pharmaceutical composition thereof. In certainembodiments, the kit of the invention includes a first containercomprising a compound described herein, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition thereof. In certainembodiments, the kits are useful in preventing and/or treating aproliferative disease in a subject. In certain embodiments, the kitsfurther include instructions for administering the compound, or apharmaceutically acceptable salt, solvate, hydrate, tautomer,stereoisomer, isotopically and labeled derivative thereof, or apharmaceutical composition thereof, to a subject to prevent and/or treata proliferative disease.

Methods of Treatment and Uses

The present invention also provides methods for the treatment orprevention of a proliferative disease (e.g., cancer, benign neoplasm,angiogenesis, inflammatory disease, autoinflammatory disease, orautoimmune disease) or an infectious disease (e.g., a viral disease) ina subject. Such methods comprise the step of administering to thesubject in need thereof an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer,stereoisomer, or isotopically labeled derivative thereof, or apharmaceutical composition thereof. In certain embodiments, the methodsdescribed herein include administering to a subject an effective amountof a compound of Formula (I), or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition thereof.

In certain embodiments, the subject being treated is a mammal. Incertain embodiments, the subject is a human. In certain embodiments, thesubject is a domesticated animal, such as a dog, cat, cow, pig, horse,sheep, or goat. In certain embodiments, the subject is a companionanimal such as a dog or cat. In certain embodiments, the subject is alivestock animal such as a cow, pig, horse, sheep, or goat. In certainembodiments, the subject is a zoo animal. In another embodiment, thesubject is a research animal such as a rodent, dog, or non-humanprimate. In certain embodiments, the subject is a non-human transgenicanimal such as a transgenic mouse or transgenic pig.

The proliferative disease to be treated or prevented using the compoundsof Formula (I) will typically be associated with aberrant activity of aCDK, and more specifically CDK7. Aberrant activity of CDK7 may be anelevated and/or an inappropriate (e.g., abnormal) activity of CDK7. Incertain embodiments, CDK7 is not overexpressed, and the activity of CDK7is elevated and/or inappropriate. In certain other embodiments, CDK7 isoverexpressed, and the activity of CDK7 is elevated and/orinappropriate. The compounds of Formula (I), and pharmaceuticallyacceptable salts, solvates, hydrates, tautomers, stereoisomers,isotopically labeled derivatives, and compositions thereof, may inhibitthe activity of CDK7 and be useful in treating and/or preventingproliferative diseases.

In other embodiments, the proliferative disease to be treated orprevented using the compounds of Formula (I) will typically beassociated with aberrant activity of CDK12. Aberrant activity of CDK12may be an elevated and/or an inappropriate (e.g., abnormal) activity ofCDK12. In certain embodiments, CDK12 is not overexpressed, and theactivity of CDK12 is elevated and/or inappropriate. In certain otherembodiments, CDK12 is overexpressed, and the activity of CDK12 iselevated and/or inappropriate. The compounds of Formula (I), andpharmaceutically acceptable salts, solvates, hydrates, tautomers,stereoisomers, isotopically labeled derivatives, and compositionsthereof, may inhibit the activity of CDK12 and be useful in treatingand/or preventing proliferative diseases.

In other embodiments, the proliferative disease to be treated orprevented using the compounds of Formula (I) will typically beassociated with aberrant activity of CDK13. Aberrant activity of CDK13may be an elevated and/or an inappropriate (e.g., abnormal) activity ofCDK13. In certain embodiments, CDK13 is not overexpressed, and theactivity of CDK13 is elevated and/or inappropriate. In certain otherembodiments, CDK13 is overexpressed, and the activity of CDK13 iselevated and/or inappropriate. The compounds of Formula (I), andpharmaceutically acceptable salts, solvates, hydrates, tautomers,stereoisomers, isotopically labeled derivatives, and compositionsthereof, may inhibit the activity of CDK13 and be useful in treatingand/or preventing proliferative diseases.

A proliferative disease may also be associated with inhibition ofapoptosis of a cell in a biological sample or subject. All types ofbiological samples described herein or known in the art are contemplatedas being within the scope of the invention. Inhibition of the activityof CDK7 is expected to cause cytotoxicity via induction of apoptosis.The compounds of Formula (I), and pharmaceutically acceptable salts,solvates, hydrates, tautomers, stereoisomers, isotopically labeledderivatives, and compositions thereof, may induce apoptosis, andtherefore, be useful in treating and/or preventing proliferativediseases.

In certain embodiments, the proliferative disease to be treated orprevented using the compounds of Formula (I) is cancer. All types ofcancers disclosed herein or known in the art are contemplated as beingwithin the scope of the invention. In certain embodiments, theproliferative disease is a cancer associated with dependence on BCL-2anti-apoptotic proteins (e.g., MCL-1 and/or XIAP). In certainembodiments, the proliferative disease is a cancer associated withoverexpression of MYC (a gene that codes for a transcription factor). Incertain embodiments, the proliferative disease is a hematologicalmalignancy. In certain embodiments, the proliferative disease is a bloodcancer. In certain embodiments, the proliferative disease is leukemia.In certain embodiments, the proliferative disease is chronic lymphocyticleukemia (CLL). In certain embodiments, the proliferative disease isacute lymphoblastic leukemia (ALL). In certain embodiments, theproliferative disease is T-cell acute lymphoblastic leukemia (T-ALL). Incertain embodiments, the proliferative disease is chronic myelogenousleukemia (CML). In certain embodiments, the proliferative disease isacute myelogenous leukemia (AML). In certain embodiments, theproliferative disease is lymphoma. In certain embodiments, theproliferative disease is melanoma. In certain embodiments, theproliferative disease is multiple myeloma. In certain embodiments, theproliferative disease is a bone cancer. In certain embodiments, theproliferative disease is osteosarcoma. In some embodiments, theproliferative disease is Ewing's sarcoma. In some embodiments, theproliferative disease is triple-negative breast cancer (TNBC). In someembodiments, the proliferative disease is a brain cancer. In someembodiments, the proliferative disease is neuroblastoma. In someembodiments, the proliferative disease is a lung cancer. In someembodiments, the proliferative disease is small cell lung cancer (SCLC).In some embodiments, the proliferative disease is large cell lungcancer. In some embodiments, the proliferative disease is a benignneoplasm. All types of benign neoplasms disclosed herein or known in theart are contemplated as being within the scope of the invention.

In some embodiments, the proliferative disease is associated withangiogenesis. All types of angiogenesis disclosed herein or known in theart are contemplated as being within the scope of the invention.

In certain embodiments, the proliferative disease is an inflammatorydisease. All types of inflammatory diseases disclosed herein or known inthe art are contemplated as being within the scope of the invention. Incertain embodiments, the inflammatory disease is rheumatoid arthritis.In some embodiments, the proliferative disease is an autoinflammatorydisease. All types of autoinflammatory diseases disclosed herein orknown in the art are contemplated as being within the scope of theinvention. In some embodiments, the proliferative disease is anautoimmune disease. All types of autoimmune diseases disclosed herein orknown in the art are contemplated as being within the scope of theinvention.

The cell described herein may be an abnormal cell. The cell may be invitro or in vivo. In certain embodiments, the cell is a proliferativecell. In certain embodiments, the cell is a blood cell. In certainembodiments, the cell is a lymphocyte. In certain embodiments, the cellis a cancer cell. In certain embodiments, the cell is a leukemia cell.In certain embodiments, the cell is a CLL cell. In certain embodiments,the cell is a melanoma cell. In certain embodiments, the cell is amultiple myeloma cell. In certain embodiments, the cell is a benignneoplastic cell. In certain embodiments, the cell is an endothelialcell. In certain embodiments, the cell is an immune cell.

In another aspect, the present invention provides methods ofdown-regulating the expression of a CDK (e.g., CDK7, CDK1, CDK2, CDK5,CDK8, CDK9, CDK12, CDK13) in a biological sample or subject. In certainembodiments, the present invention provides methods of down-regulatingthe expression of CDK7 in a biological sample or subject. In anotheraspect, the present invention provides methods of down-regulating theexpression of IRAK1, JNK1, JNK2, or MLK3 in a biological sample orsubject.

Another aspect of the invention relates to methods of inhibiting theactivity of a kinase in a biological sample or subject. In certainembodiments, the kinase is CDK. In certain embodiments, the kinase isCDK7. In other embodiments, the kinase is CDK12 or CDK13. In certainembodiments, the activity of the kinase is aberrant activity of thekinase. In certain embodiments, the inhibition of the activity of thekinase is irreversible. In other embodiments, the inhibition of theactivity of the kinase is reversible. In certain embodiments, themethods of inhibiting the activity of the kinase include attaching acompound of Formula (I) to the kinase.

In certain embodiments, the methods described herein comprise theadditional step of administering one or more additional pharmaceuticalagents in combination with the compound of Formula (I), apharmaceutically acceptable salt thereof, or compositions comprisingsuch compound or pharmaceutically acceptable salt thereof. Suchadditional pharmaceutical agents include, but are not limited to,anti-proliferative agents, anti-cancer agents, anti-diabetic agents,anti-inflammatory agents, immunosuppressant agents, and a pain-relievingagent. The additional pharmaceutical agent(s) may synergisticallyaugment inhibition of CDK7, CDK12, or CDK13 induced by the inventivecompounds or compositions of this invention in the biological sample orsubject. In certain embodiments, the additional pharmaceutical agent isflavopiridol, triptolide, SNS-032 (BMS-387032), PHA-767491, PHA-793887,BS-181, (S)—CR8, (R)—CR8, or NU6140. In certain embodiments, theadditional pharmaceutical agent is an inhibitor of a mitogen-activatedprotein kinase (MAPK). In certain embodiments, the additionalpharmaceutical agent is an inhibitor of a glycogen synthase kinase 3(GSK3). In certain embodiments, the additional pharmaceutical agent isan inhibitor of an AGC kinase. In certain embodiments, the additionalpharmaceutical agent is an inhibitor of a CaM kinase. In certainembodiments, the additional pharmaceutical agent is an inhibitor of acasein kinase 1. In certain embodiments, the additional pharmaceuticalagent is an inhibitor of a STE kinase. In certain embodiments, theadditional pharmaceutical agent is an inhibitor of a tyrosine kinase.Thus, the combination of the inventive compounds or compositions and theadditional pharmaceutical agent(s) may be useful in treatingproliferative diseases resistant to a treatment using the additionalpharmaceutical agent(s) without the inventive compounds or compositions.

In some embodiments, the one or more additional pharmaceutical agentsare independently selected from a topoisomerase inhibitor, a MCL1inhibitor, a BCL-2 inhibitor, a BCL-xL inhibitor, a BRD4 inhibitor, aCDK9 inhibitor, a Jumonji histone demethylase inhibitor, and a DNAdamage inducer. In a more specific aspect of these embodiments, the oneor more additional agents is selected from etoposide, obatoclax,navitoclax, JQ1,4-(((5′-chloro-2′-(((1R,4R)-4-(((R)-1-methoxypropan-2-yl)amino)cyclohexyl)amino)-[2,4′-bipyridin]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile,JIB04 and cisplatin. In an even more specific aspect of theseembodiments, the additional agent is selected from etoposide, obatoclax,and navitoclax and the disease to be treated is breast cancer, e.g.,triple-negative breast cancer, HER2 positive breast cancer, ER-positivebreast cancer, or ER/PR-positive breast cancer. In another even morespecific aspect of these embodiments, the additional agent is selectedfrom etoposide, JIB04 and cisplatin and the disease to be treated isEwing's sarcoma. In still another even more specific aspect of theseembodiments, the additional agent is selected from JQ1 and NVP2, and thedisease to be treated is leukemia, e.g., acute myelogenous leukemia,myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia,monocytic leukemia, monoblastic leukemia, or megakaryoblastic leukemia.

In yet another aspect, the present invention provides the compounds ofFormula (I), and pharmaceutically acceptable salts, solvates, hydrates,tautomers, stereoisomers, isotopically labeled derivatives, andcompositions thereof, for use in the treatment of a proliferativedisease in a subject. In certain embodiments, provided by the inventionare the compounds described herein, and pharmaceutically acceptablesalts and compositions thereof, for use in the treatment of aproliferative disease in a subject. In certain embodiments, provided bythe invention are the compounds described herein, and pharmaceuticallyacceptable salts and compositions thereof, for use in inhibiting cellgrowth. In certain embodiments, provided by the invention are thecompounds described herein, and pharmaceutically acceptable salts andcompositions thereof, for use in inducing apoptosis in a cell. Incertain embodiments, provided by the invention are the compoundsdescribed herein, and pharmaceutically acceptable salts and compositionsthereof, for use in inhibiting transcription.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions, and methodsprovided herein and are not to be construed in any way as limiting theirscope.

The compounds provided herein can be prepared from readily availablestarting materials using modifications to the specific synthesisprotocols set forth below that would be well known to those of skill inthe art. It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvents used, butsuch conditions can be determined by those skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in Greene et al., Protecting Groups inOrganic Synthesis, Second Edition, Wiley, New York, 1991, and referencescited therein.

ABBREVIATIONS Ac acetyl ACN acetonitrile aq. aqueous atm atmospheres Boctert-butoxy carbonyl Boc₂O Di-t-butyl dicarbonate DCCN,N′-Dicyclohexylcarbodiimide DCM dichloromethane DIPEA N,N-Diisopropylethylamine DMF Dimethylformamide DMSO dimethylsulfoxide EDTAethylenediamine tetraacetic acid eq(s). equivalent(s) Et Ethyl EtOAcethyl acetate EtOH ethanol Et₃N triethylamine g gram(s) H; H hour(s)HATU (Dimethylamino)-N,N- dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate HBTUO-Benzotriazole-N,N,N′,N′- tetramethyl-uronium-hexafluoro- phosphate Hexhexane HPLC High pressure liquid chromatography IPA isopropanol LCMS;liquid chromatography mass LC-MS spectrometry MeOH methanol mgmilligram(s) min Minute(s) mL; ml milliliter(s) MS mass spectrometry mWmicrowave NMP N-Methyl-2-pyrrolidone NMR Nuclear magnetic resonance Phphenyl r.t.; rt; Room temperature RT S.; sat. saturated TFAtrifluoroacetic acid THF tetrahydrofuran TLC Thin layer chromatographyX-Phos 2-Dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl

Example 1 Synthesis of(E)-N-(4-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide(Compound 100)p-{[3-(Benzyloxycarbonylamino)-1-piperidyl]carbonyl}phenylamino2,2-dimethylpropionate

To a solution of 4-(tert-butoxycarbonylamino)benzoic acid (438 mg, 1.8mmol), 3-CBz-aminopiperidine.HCl (500 mg, 1.8 mmol) and Et₃N (0.89 ml,5.5 mmol) in DMF (10 mL) was added HBTU (1.05 g, 2.8 mmol). The mixturewas stirred 5 h at rt before being diluted with EtOAc (100 ml), washedwith water (100 mL), brine (3×100 mL), dried (MgSO₄), filtered andconcentrated under reduced pressure. The mixture was purified by SiO₂chromatography (Hex/EtOAc 20 to 100% gradient) and afforded the titlecompound (765 mg, 1.69 mmol, 94%) as a colorless oil.

tert-butyl 4-(3-aminopiperidine-1-carbonyl)phenylcarbamate

To a degassed solution ofp-{[3-(Benzyloxycarbonylamino)-1-piperidyl]carbonyl}phenylamino2,2-dimethylpropionate (765 mg, 1.69 mmol) in MeOH (25 mL) was added 10%Pd/C (60 mg). The mixture was stirred 1h under H₂ (1 atm) before beingfiltered over Celite® (MeOH). The volatiles were removed under reducedpressure to afford the title compound (510 mg, 1.60 mmol, 94.7%) as awhite solid which was used in the next step without furtherpurification.

tert-butyl4-(3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)piperidine-1-carbonyl)phenylcarbamate

A suspension of3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (0.524 g,1.3 mmol), tert-butyl 4-(3-aminopiperidine-1-carbonyl)phenylcarbamate(414 mg, 1.3 mmol) and DIPEA (452 uL, 2.59 mmol) in NMP (5 mL) washeated at 140° C. (mW) for 20 min. The cooled mixture was diluted withEtOAc (20 mL), washed with sat. NaHCO₃ (5 mL), brine (5 mL), dried(MgSO₄), filtered and concentrated under reduced pressure. The residuewas purified by SiO₂ chromatography (Hex/EtOAc 35 to 100% gradient) toafford the title compound (570 mg, 0.83 mmol, 64%) as a white solid.

(4-aminophenyl)(3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)piperidin-1-yl)methanone

A solution of tert-butyl4-(3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)piperidine-1-carbonyl)phenylcarbamate(570 mg, 0.829 mmol) in DCM (5 mL) was treated with TFA (2 mL). Themixture was stirred 30 min at rt before being concentrated under reducedpressure and diluted with DCM (10 mL), washed with sat. NaHCO₃ (5 mL),dried (MgSO₄), filtered, and concentrated under reduced pressure toafford the title compound (461 mg, 0.785 mmol, 95%) as white solid.

(E)-N-(4-(3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide

To a −60° C. solution of(4-aminophenyl)(3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)piperidin-1-yl)methanone(60 mg, 0.102 mmol) and DIPEA (53 ul, 0.310 mmol) in DMF (1 mL) wasslowly added a 74 mg/mL solution of (E)-4-bromobut-2-enoyl chloride inDCM (256 uL, 0.102 mmol). After 30 min at −60° C., a 2M solution ofdimethylamine in THF (60 uL, 0.120 mmol) was added and the resultingmixture was warmed to room temp and stirred for 1 hr. The solution wasdiluted with CHCl₃ (25 ml), washed with water (5 mL), dried (MgSO₄),filtered and concentrated under reduced pressure to afford the titlecompound (71 mg, 0.102 mmol, 100%) as a yellowish solid which was usedin the next step without further purification.

(E)-N-(4-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide(Compound 100)

A solution of(E)-N-(4-(3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide(71 mg, 0.102 mmol) in dioxane (2 mL) and 5M NaOH (500 uL, 2.55 mmol)was heated 3 h at 75° C. The cooled mixture was diluted with DCM (10mL), washed with water (3 mL), dried (MgSO₄), filtered and concentratedunder reduced pressure. The mixture was purified by reverse phasechromatography (C18, water/ACN, 20 to 100% gradient) to afford Compound100 (5 mg, 0.009 mmol, 10%) as a white solid after lyophilisation. ¹HNMR (500 MHz, DMSO) δ 11.87 (s, 1H), 10.42-10.02 (m, 2H), 8.82-8.59 (m,1H), 8.47 (s, 1H), 8.30 (s, 1H), 7.87-7.59 (m, 2H), 7.49 (t, J=19.2 Hz,1H), 7.37 (m, 2H), 7.27-7.04 (m, 2H), 6.80 (dt, J=15.7, 12.9 Hz, 2H),6.30 (d, J=16.3 Hz, 2H), 4.19-3.66 (m, 4H), 3.87 (s, 1H), 3.10 (d, J=5.9Hz, 2H), 2.21 (s, 3H), 2.14-2.03 (m, 1H), 1.80-1.63 (m, 1H), 1.59 (m,1H); MS (m/z): 558.66 [M+1]⁺.

Example 2 Synthesis of(E)-N-(4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)methyl)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide(Compound 101) tert-butyl3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)methyl)piperidine-1-carboxylate

A solution of3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (300 mg,0.74 mmol), 1-Boc-3-(aminomethyl)piperidine (159 mg, 0.74 mmol) anddiisopropylethylamine (0.13 mL, 0.74 mmol) in NMP (2.0 mL) was heated 25min at 135° C. (mW). The mixture was diluted with EtOAc (30 mL), washedwith water (3×5 mL), brine (5 mL), dried (MgSO₄), filtered, andconcentrated under reduced pressure. The residue was purified by SiO₂chromatography (DCM/EtOAc 0 to 15% gradient), and afforded the titlecompound (355 mg, 0.67 mmol, 85%) as a white solid.

5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-N-(piperidin-3-ylmethyl)pyrimidin-2-amine

Trifluoroacetic acid (0.93 mL, 12.2 mmol) was added to a stirringsolution of tert-butyl3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)methyl)piperidine-1-carboxylate(355 mg, 0.67 mmol) in DCM (2.7 mL) at 0° C. The resulting solution wasstirred 1 h at rt, concentrated under reduced pressure, and diluted withDCM (20 mL) and sat NaHCO₃ (10 mL). The phases were separated and theaqueous layer was extracted with DCM (2×15 mL). The combined organicslayers were dried (MgSO₄), filtered, and concentrated to afford thetitle compound (324 g, 0.67 mmol, 100%) as a yellow foam which was usedin the next step without further purification.

tert-butyl4-(3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)methyl)piperidine-1-carbonyl)phenylcarbamate

A solution of5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-N-(piperidin-3-ylmethyl)pyrimidin-2-amine(273 mg, 0.57 mmol), 4-(tert-butoxycarbonylamino)benzoic acid (134 mg,0.57 mmol), HBTU (644 mg, 1.7 mmol), and diisopropylethylamine (0.30 mL,1.70 mmol) in DCM (2.5 mL) was stirred overnight at rt. The mixture wasconcentrated under reduced pressure and the residue was used in the nextstep without further purification.

(4-aminophenyl)(3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)methyl)piperidin-1-yl)methanonetrifluoroacetic acid salt

A solution of crude tert-butyl4-(3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)methyl)piperidine-1-carbonyl)phenylcarbamate(349 mg, 0.498 mmol) DCM (5 mL) was treated with TFA (381 uL, 4.98 mmol)and stirred overnight at rt. The mixture was concentrated under reducedpressure, diluted with toluene (5 mL), and concentrated under reducedpressure again. The same process was repeated three times and affordedthe title compound as a pale orange foam which was used in the next stepwithout further purification.

(4-aminophenyl)(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)methyl)piperidin-1-yl)methanone

A solution of(4-aminophenyl)(3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)methyl)piperidin-1-yl)methanonetrifluoroacetic acid salt (356 mg, 0.498 mmol) and 5M NaOH (1.49 mL,7.47 mmol) in dioxane (8.0 mL) was heated 3.5 h at 70° C. The cooledmixture was diluted with DCM/MeOH 10/1 (15 mL) and washed with water (5mL). The water layer was extracted with DCM/MeOH 10:1 (3×10 mL) and thecombined organics were dried (MgSO₄), filtered and evaporated underreduced pressure. The residue was purified by reverse phasechromatography (H₂O/ACN+0.1% formic acid 15 to 60% gradient), andafforded the title compound (219 mg, 0.48 mmol, 83% over 3 steps) as awhite solid.

(E)-N-(4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)methyl)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide

To a cold solution (−60° C.) of(4-aminophenyl)(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)methyl)piperidin-1-yl)methanone(185 mg, 0.401 mmol) and DIPEA (210 μL, 1.20 mmol) in THF (2.5 mL) wasadded a 55.6 mg/mL solution of (E)-4-bromobut-2-enoyl chloride (547 uL,0.401 mmol) in THF. After 1.5 h at (−60° C.), a 2M solution ofdimethylamine in THF (802 uL, 1.61 mmol) was added and the mixture wasstirred 24 h at −30° C. NMP (2 mL) was added, followed by removal of theTHF under reduced pressure. The residue was purified by reverse phasechromatography (0.1% HCOOH, H₂O/ACN 15 to 60% gradient) and affordedCompound 101 (53 mg, 0.093 mmol, 23%) as a light yellow solid afterlyophilisation. ¹H NMR (500 MHz, DMSO) δ 11.83 (s, 1H), 10.20 (s, 1H),8.56 (br s, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 7.72-7.55 (m, 2H), 7.49 (d,J=7.9 Hz, 2H), 7.38-6.97 (m, 4H), 6.74 (dd, J=13.6, 7.4 Hz, 1H), 6.28(d, J=15.6 Hz, 1H), 4.46 (br s, 1H), 4.15 (br s, 1H), 3.16 (d, J=4.3 Hz,2H), 3.04-2.86 (m, 2H), 2.74-2.56 (m, 1H), 2.37 (d, J=9.0 Hz, 1H), 2.25(s, 6H), 2.03-1.81 (m, 2H), 1.76-1.59 (m, 1H), 1.46-1.22 (m, 2H); MS(m/z): 572.65 [M+1]⁺.

Example 3 Synthesis of(E)-3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-N-(4-(4-(dimethylamino)but-2-enamido)phenyl)piperidine-1-carboxamide(Compound 102)5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-2-amine

To a solution of 3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (402 mg) in 1,2-dimethoxylmethanol was added tert-butyl3-aminopiperidine-1-carboxylate (200 mg, 1.0 equiv) anddiisopropylethylamine (129 mg, 1.0 equiv). The solution was heated for 2h at 120° C. The cooled solution was diluted with 100 mL of CHCl₃ andi-PrOH(4:1) and then washed with water. After removing solvent, thecrude product was dissolved in 10 mL CHCl₃ and treated with 5 mL TFA.After stirring for 30 min at room temperature, the solvent was removedand the product was purified byby silica gel chromatography withCH₂Cl₂/methanol (10:1) to give the product (350 mg, 76%).

3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-N-(4-nitrophenyl)piperidine-1-carboxamide

To a stirred solution of the5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-2-amine(350 mg) in 10 mL CH₂Cl₂ was added 1-isocyanato-4-nitrobenzene (123 mg,1.0 equiv) at room temperature. The reaction mixture was stirred for 2 hand concentrated under reduced pressure. The resulting crude product waspurified by flash column chromatography with CH₂Cl₂/methanol (10:1) toprovide the title compound (375 mg, 80%).

N-(4-aminophenyl)-3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxamide

The nitro compound (375 mg) was suspended in 30 mL of ethylacetate/methanol (5:1) and treated with SnCl₂ (280 mg, 2.5 equiv). Afterstirring for 2 h at 80° C., the reaction mixture was cooled to roomtemperature and poured into saturated aqueous NaHCO₃. The mixture wasstirred for 10 min and the aqueous phase was then extracted with 100 mLchloroform and 2-propanol (4:1). The combined organic layer was washedwith water and brine, dried over MgSO₄, filtered through a pad ofCelite® and concentrated under reduced pressure. The resulting crudeproduct was purified by flash column chromatography with CH₂Cl₂/methanol(10:1) to provide the title compound (210 mg, 60%).

(E)-3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-N-(4-(4-(dimethylamino)but-2-enamido)phenyl)piperidine-1-carboxamide(Compound 102)

To the solution of the aniline (60 mg) in 10 mL of acetonitrile wasadded diisopropylethylamine (13 mg, 1.0 equiv). The reaction mixture wascooled to 0° C. and then treated with 4-chlorobut-2-enoyl chloride (54mg, 3.0 equiv) in CH₂Cl₂. The reaction mixture was stirred for 10 min at0° C. and then treated with a solution of dimethylamine in THF. Thereaction mixture was then warmed to room temperature, stirred for 1 h,and concentrated under reduced pressure. The resulting crude product waspurified by preparative HPLC. The resulting product then was dissolvedin 5 mL 1,4-dioxane and 5 mL 1M NaOH. The solution was allowed to stirat room temperature for 2 h and then 5 mL 1M HCl was added. The solutionwas then diluted with 30 mL of chloroform and 2-propanol (4:1), followedby washing the organic layer with water. The removal of solvent providedthe crude product, which was purified by HPLC to give the final productCompound 102 (25 mg, 43%). MS (m/z): 573 [M+1]⁺.

Example 4 Synthesis of(R,E)-N-(4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide(Compound 103) (R)-tert-butyl3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

3-(2,5-dichloropyrimidine-4-yl)-1-1-(phenylsulfonyl)-1H-indole (403 mg,1.0 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (400 mg,2.0 equiv) were dissolved in NMP (5 mL). After heating at 80° C. for 3hours, the solution was cooled to room temperature and then diluted withethyl acetate (100 mL). The resulted solution was washed with saturatedNaHCO₃, water, and brine. After drying with MgSO₄, the solvent wasremoved and the product was obtained by flash chromatography withdichloromethane/methanol (10:1) as eluent. (397.0 mg, yield 70%) MS(m/z): 568 [M+1]⁺.

(R)-5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)-N-(piperidin-3-yl)pyrimidin-2-amine

(R)-tert-butyl3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylatewas dissolved in 4 mL of dichloromethane and 2 mL of trifluoroaceticacid. The solvent was removed with reduced pressure to give the crudeproduct which was used in next step directly.

(R)-(3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)(4-nitrophenyl)methanone

To a pyridine solution of the free amine (47.0 mg, 0.1 mmol) was addedbenzoyl chloride (22.0 mg, 1.2 equiv). After stirring for 2 hours at 80°C., the reaction mixture was concentrated and the crude was purified byHPLC to give the pure product as a TFA salt. (52 mg, 80%) MS (m/z): 617[M+1]⁺.

(R)-(4-aminophenyl)(3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidin-1-yl)methanone

The nitro compound (52 mg, 0.080 mmol) was suspended in ethylacetate/methanol (5:1, vol/vol, 10 mL) and the resulted suspension wastreated with SnCl₂ (40 mg, 2.5 equiv). After stirring for 2 hours at 80°C., the reaction mixture was cooled to room temperature and then waspoured into a saturated NaHCO₃ solution (10 mL). The mixture was stirredfor 10 minutes and then was extracted with chloroform/2-propanol (4:1,vol/vol, 50 mL). The organic layer was washed with water and brine,dried over MgSO₄, filtered through a pad of Celite® and concentratedunder reduced pressure. The crude was purified by HPLC to provide theproduct (32 mg, 61%). MS (m/z): 587 [M+1]⁺.

(R,E)-N-(4-(3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide

To a solution of the free amine (60 mg, 0.11 mmol) in acetonitrile (5mL) was added N,N-diisopropylethylamine (40 uL) and(E)-4-bromobut-2-enoyl chloride (40 mg, 2.0 equiv) in dichloromethane (1mL) at 0° C. dropwise. After stirring for 5 minutes, dimethylamine (1Min THF, 2 mL) was added and the solution was allowed to stir at roomtemperature for 2 hours. The solvent was then removed and the crude waspurified by HPLC to give the product (58 mg, 82%). MS (m/z): 698 [M+1]⁺.

(R,E)-N-(4-(3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide

To a solution of(R,E)-N-(4-(3-((5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide(58 mg, 0.08 mmol) in 1,4-dioxane (2 mL) was added 1.0 M NaOH (2 mL).The solution was stirred at room temperature for 2 hours and then wasquenched with 1.0 M HCl (2 mL). The solution was extracted withchloroform/2-propanol (4/1, vol/vol, 20 mL) and the organic layer waswashed with water, brine and dried with MgSO₄. The sovlent was removedunder reduced pressure and the crude was purified by HPLC to provideCompound 103 as a TFA salt. (33 mg, 72%)¹H NMR (600 MHz, DMSO-d6): 11.83(s, 1H), 10.44 (s, 1H), 9.82 (s, 1H), 8.60-8.20 (m, 2H), 7.64 (m, 2H),7.47 (d, J=8.4 Hz, 1H), 7.35 (m, 2H), 7.18 (m, 1H), 7.12 (s, 1H), 6.74(m, 1H) 6.43 (d, J=14.4 Hz, 1H), 3.90 (d, J=7.2 Hz, 2H), 3.80-3.50 (m,3H), 3.20-3.08 (m, 2H), 2.66 (s, 6H), 2.05 (s, 1H), 2.00-1.70 (m, 1H),1.64 (s, 1H), 1.52 (m, 1H). MS (m/z): 558 [M+1]⁺.

Example 5 Synthesis of Additional Compounds of the Invention

Additional compounds of the invention were synthesized in the manneroutlined in Example 4. The ¹H NMR and MS characterization data for thesecompounds are indicated in the table below.

Compound Number ¹H NMR [M + 1]⁺ 104 558 105 558 106 ¹H NMR (600 MHz,DMSO-d6) 11.82 (s, 1H), 588 10.47 (s, 1H), 9.82 (s, 1H), 8.65-8.28 (m,2H), 8.01-7.55 (m, 2H), 7.46 (d, J = 7.8 Hz, 1 H), 7.45-7.25 (m, 2H),7.17 (m, 1H), 7.13 (m, 1H), 6.72 (m, 1H), 6.43 (m, 1H), 3.92 (m, 2H),3.90-3.50 (m, 3H), 3.20-3.00 (m, 2H) 2.78 (s, 6H), 2.09-1.50 (m, 4H) 107572 108 572

Example 6 Kinase Activity

Compounds of the invention were assayed for activity against a varietyof different kinases at Life Technologies™ (Grand Island, N.Y.) usingtheir commercially available Adapta® (for CDK7, CDK9/cyclin T1, andIRAK1 kinases), Z′-Lyte® (for CDK1, CDK2, CDK5/p25, CDK5/p35, JNK1 andJNK2 kinases) and LanthaScreen Eu® (for CDK8, CDK9/cyclin K and MLK3)kinase assay services. Test compounds were tested at 100 nM and 1 μMfinal concentrations in 1% DMSO against all kinases except CDK7. ForCDK7, test compounds were tested at concentrations ranging from 10 μMdown to 0.514 nM in a series of 3-fold serial dilutions. Details ofthese assays, including substrates used for each kinase, are availableon the Life Technologies web site(http://www.lifetechnologies.com/us/en/home/life-science/drug-discovery/target-and-lead-identification-and-validation/kinasebiology/kinase-activity-assays.html).The results of the assay are shown below in Tables 2A and 2B. In Tables2A and 2B, for CDK7 activity, “A” represents a calculated IC₅₀ of lessthan 100 nM; “B” represents a calculated IC₅₀ of between 100 nM and 1μM; and “C” represents a calculated IC₅₀ of greater than 1 μM. For allother tested kinases, “A” represents greater than a 70% inhibition ofthat kinase by the test compound, “B” represents between a 50% and 70%inhibition; and “C” represents less than a 50% inhibition. Theco-factors used for each kinase in the assays were as followsCDK1—cyclin B; CDK2—cyclin A; CDK5—p25 or p35 as indicated; CDK7—cyclinH and MNAT1; CDK8—cyclin C; CDK9—cyclin K or cyclin T1 as indicated;IRAK1—Histone H3 (1-20) peptide; JNK1—none required; JNK2—none required;MLK3—none required.

TABLE 2A Activity of Selected Compounds of the Invention Against VariousKinases Compound No. CDK7 CDK1^(a) CDK1^(b) CDK2^(a) CDK2^(b) CDK5^(a,c)CDK5^(b,c) CDK5^(a,d) CDK5^(b,d) CDK8^(a) CDK8^(b) 100 B 101 B C C C C CC C C C C 102 B

TABLE 2B Activity of Selected Compounds of the Invention Against VariousKinases Compound No. CDK9^(a,e) CDK9^(b,e) CDK9^(a,f) CDK9^(b,f)JNK1^(a) JNK1^(b) JNK2^(a) JNK2^(b) MLK3^(a) MLK3^(b) 100 101 C C C C BA C ACompound 100 was tested against CDK5 using p25 as a co-factor andagainst MLK3. Although a percent inhibition was not determined, Compound100 was calculated to have a 3.0 μM IC₅₀ against CDK5 and a 3.2 μM C₅₀against MLK3. ^(a) Compound tested at 100 nM^(b) Compound tested at 1μM^(c) CDK5 tested using p25 co-factor^(d) CDK5 tested using p35co-factor^(e) CDK9 tested using cyclin T1 co-factor^(f) CDK9 testedusing cyclin K co-factor

Example 7 Inhibition of Cell Proliferation

Representative compounds of the invention were tested at differentconcentrations (from 10 μM to 316 pM; 0.5 log serial dilutions) fortheir ability to inhibit the proliferation of Jurkat cells. Cells weregrown in RPMI 1640+10% FBS+1% Glutamax supplemented with FBS (LifeTechnologies) and 100 U·mL⁻¹ penicillin, 100 μg·mL⁻¹ streptomycin(Invitrogen) and cultured at 37° C. in a humidified chamber in thepresence of 5% CO₂. Proliferation assays were conducted over a 72 hourtime period. CellTiter-Glo® (Promega Corporation, Madison, Wis. USA) wasused to assess the anti-proliferative effects of the compounds followingmanufacturer's directions and utilizing the reagents supplied with theCellTiter-Glo® kit. The results of these assays are set forth in Tables3, below. In this table, “A” represents an IC₅₀ of less than 500 nM; “B”an IC₅₀ of between 500 nM and 5 μM; and “C” an IC₅₀ of greater than 5μM.

TABLE 3 Inhibition of Proliferation of Jurkat Cells by Compounds of theInvention. Compound Jurkat 100 A 101 B

Equivalents and Scope

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1. A compound having the structural formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, orstereoisomer thereof, wherein: ring A is an optionally substitutedheteroaryl ring of any one of the Formulae (i-1)-(i-6):

wherein: each instance of V¹, V², V³, V⁴, V⁵, V⁶, V⁷, V⁸, V⁹, V¹⁰, V¹¹,V¹², V¹³, V¹⁴ and V¹⁵ is independently O, S, N, N(R^(A1)), C, orC(R^(A2)); each instance of R^(A1) is independently selected fromhydrogen, deuterium, optionally substituted acyl, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl; eachinstance of R^(A2) is independently selected from hydrogen, deuterium,halogen, —CN, optionally substituted acyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(A2a), —N(R^(A2a))₂, and —SR^(A2a) wherein each occurrence ofR^(A2a) is independently selected from hydrogen, optionally substitutedacyl, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl, or any two R^(A1), any two R^(A2), orone R^(A1) and one R^(A2) are joined to form an optionally substitutedcarbocyclic, optionally substituted heterocyclic, optionally substitutedaryl, or optionally substituted heteroaryl ring; each X is independentlyselected from N and CH, wherein at least one X is N; W is selected fromN and C(R^(1a)); each of R^(1a), if present, and R^(1b) is independentlyselected from hydrogen, deuterium, halogen, optionally substituted acyl,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —OR^(B1a), —N(R^(B1a))₂, and —SR^(B1a),wherein each occurrence of R^(B1a) is independently selected fromhydrogen, optionally substituted acyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, orR^(1a) and R^(1b) are joined to form an optionally substitutedcarbocyclic, optionally substituted heterocyclic, optionally substitutedaryl, or optionally substituted heteroaryl ring; R² is an optionallysubstituted C₁-C₄ alkylene or an optionally substituted C₂-C₄ alkenyleneor alkynylene, wherein one or more methylene units of the alkylene,alkenylene or alkynylene are optionally and independently replaced with—O—, —S—, or —N(R⁶)—; each instance of R³, if present, is independentlyselected from deuterium, halogen, optionally substituted acyl,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —OR^(C1), —N(R^(C1))₂, and —SR^(C1), whereineach occurrence of R^(C1) is independently selected from hydrogen,optionally substituted acyl, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or two R³groups bound to the same ring carbon atom are taken together to form ═O,or two R³ groups bound to the same or different ring carbon atoms arejoined to form an optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl ring; R⁴ is selected from a bond, an optionallysubstituted C₁-C₄ alkylene, and an optionally substituted C₂-C₄alkenylene or alkynylene, wherein: one or more methylene units of thealkylene, alkenylene or alkynylene other than a methylene unit bound toa nitrogen atom is optionally and independently replaced with —O—, —S—,—N(R⁶)—, or —S(═O)₂—, and two substituents on either the same oradjacent carbon atoms in the alkylene, alkenylene or alkynylene aretaken together to form an optionally substituted carbocyclic oroptionally substituted heterocyclic ring; each R⁶ is independentlyselected from hydrogen, and —C₁-C₆ alkyl; R⁷ is any one of the Formulae(ii-1)-(ii-20):

wherein: L³ is a bond, an optionally substituted C₁-C₄ alkylene, or anoptionally substituted C₂-C₄ alkenylene or alkynylene, wherein one ormore methylene units of the alkylene, alkenylene or alkynylene areoptionally and independently replaced with —O—, —S—, or —N(R⁶)—; L⁴ is abond, an optionally substituted C₁-C₄ alkylene, or an optionallysubstituted C₂-C₄ alkenylene or alkynylene; R^(E1) is selected from thegroup consisting of hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl, —CN,—CH₂OR^(E1a), —CH₂N(R^(E1a))₂, —CH₂SR^(E1a), —OR^(E1a), —N(R^(E1a))₂,—Si(R^(E1a))₃, and —SR^(E1a), wherein each occurrence of R^(E1a) isindependently selected from the group consisting of hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or two R^(E1a) groups are joined to form anoptionally substituted heterocyclic ring; R^(E2) is selected from thegroup consisting of hydrogen, halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl, —CN,—CH₂OR^(E2a), —CH₂N(R^(E2a))₂, —CH₂SR^(E2a), —OR^(E2a), —N(R^(E2a))₂,and —SR^(E2a), wherein each occurrence of R^(E2a) is independentlyselected from the group consisting of hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, ortwo R^(E2a) groups are joined to form an optionally substitutedheterocyclic ring; R^(E3) is selected from the group consisting ofhydrogen, halogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, —CN, —CH₂OR^(E3a),—CH₂N(R^(E3a))₂, —CH₂SR^(E3a), —OR^(E3a), —N(R^(E3a))₂, and —SR^(E3a),wherein each occurrence of R^(E3a) is independently selected from thegroup consisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or two R^(E3a)groups are joined to form an optionally substituted heterocyclic ring;optionally R^(E1) and R^(E3), or R^(E2) and R^(E3), or R^(E1) and R^(E2)are joined to form an optionally substituted carbocyclic or optionallysubstituted heterocyclic ring; R^(E4) is a leaving group; R^(E5) isselected from the group consisting of hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —CH₂OR^(E5a), —CH₂N(R^(E5a))₂,—CH₂SR^(E5a), —OR^(E5a), —N(R^(E5a))₂, and —SR^(E5a), wherein eachoccurrence of R^(E5a) is independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or two R^(E5a)groups are joined to form an optionally substituted heterocyclic ring; Yis O, S, or NR^(E6), wherein R^(E6) is hydrogen, substituted orunsubstituted C₁₋₆ alkyl, or a nitrogen protecting group; a is 1 or 2; zis 0, 1, 2, 3, 4, 5, or 6; each instance of R⁸, if present, isindependently selected from deuterium, halogen, optionally substitutedacyl, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —OR^(D1), —N(R^(D1))₂, and —SR^(D1),wherein each occurrence of R^(D1) is independently selected fromhydrogen, optionally substituted acyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,and optionally substituted aryl, optionally substituted heteroaryl, ortwo R⁸ groups are joined to form an optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl, oroptionally substituted heteroaryl ring; m is 0, 1, 2, 3 or 4; and n is0, 1, 2, 3, 4, 5 or
 6. 2. The compound of claim 1, wherein ring A is


3. The compound of claim 1, wherein each of R^(1a) is chloro.
 4. Thecompound of claim 1, wherein R^(1b) is hydrogen.
 5. The compound ofclaim 1, wherein W is C(R^(1a)).
 6. The compound of claim 1, whereineach X is N.
 7. The compound of claim 1, wherein R² is selected from —NHand —NH—CH₂-**, wherein “**” represents a portion of R² bound topiperidin-1,3-diyl.
 8. The compound of claim 1, wherein n is
 0. 9. Thecompound of claim 1, wherein R⁴ is —C(O)—, ^(††)—C(O)—NH—, or —CH₂,wherein “††” represents a portion of R⁴ bound to piperidin-1,3-diyl. 10.The compound of claim 1, wherein each R⁶ is hydrogen.
 11. The compoundof claim 1, wherein R⁷ is located para or meta to R⁴.
 12. The compoundof claim 11, wherein R⁷ is located para to R⁴.
 13. The compound of claim11, wherein R⁷ is located meta to R⁴.
 14. The compound of claim 11,wherein R⁷ is 4-dimethylaminobut-2-enamido.
 15. The compound of claim 1,wherein m is 0 or
 1. 16. The compound of claim 1, wherein R⁸ isoptionally substituted alkyl.
 17. The compound of claim 16, wherein R ismethyl.
 18. The compound of claim 1, selected from any one of:

and pharmaceutically acceptable salts, solvates, hydrates, tautomers,stereoisomers, and isotopically labeled derivatives of the foregoing.19. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable excipient.
 20. A method of treating asubject suffering from a disease or condition associated with aberrantactivity of a cyclin-dependent kinase (CDK) comprising the step ofadministering to the subject in need thereof a composition of claim 19.21. The method of claim 20, wherein the CDK is CDK7.
 22. The method ofclaim 20, wherein the disease or condition is selected from cancer,benign neoplasm, angiogenesis, inflammatory disease, autoinflammatorydisease, autoimmune disease, or an infectious disease.
 23. The method ofclaim 20, wherein the subject is a mammal.
 24. The method of claim 20,wherein the disease is cancer.
 25. The method of claim 24, wherein thecancer is selected from a blood cancer, melanoma, a bone cancer, abreast cancer, a brain cancer, or a lung cancer.
 26. The method of claim25, wherein the cancer is a blood cancer selected from chroniclymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cellacute lymphoblastic leukemia (T-ALL), chronic myelogenous leukemia(CML), acute myelogenous leukemia (AML), lymphoma, and multiple myeloma.27. The method of claim 25, wherein the disease is a bone cancerselected from osteosarcoma and Ewing's sarcoma.
 28. The method of claim25, wherein the disease is triple-negative breast cancer (TNBC).
 29. Themethod of claim 25, wherein the disease is neuroblastoma.
 30. The methodof claim 25, wherein the disease is small cell lung cancer (SCLC). 31.The method of claim 20, comprising the additional step of administeringto the subject in need thereof one or more additional agentsindependently selected from anti-proliferative agents, anti-canceragents, immunosuppressant agents, and pain-relieving agents.
 32. Themethod of claim 24, comprising the additional step of administering tothe subject in need thereof one or more additional agents independentlyselected from a topoisomerase inhibitor, a MCL1 inhibitor, a BCL-2inhibitor, a BCL-xL inhibitor, a BRD4 inhibitor, a CDK9 inhibitor, aJumonji histone demethylase inhibitor, and a DNA damage inducer.